Abstract
Background: Microsomal prostaglandin E synthase-1 (mPGES-1)-derived prostaglandin E2 (PGE2) is a chief mediator of inflammation. However, the role and mechanism of mPGES-1 in peritoneal dialysis (PD)-associated peritoneal fibrosis have not been investigated.Material and Methods: In PD patients, mPGES-1 expression in peritoneum tissues and the levels of PGE2, IL-1β, and IL-18 in the dialysate were examined. In rat peritoneal mesothelial cells (RPMCs), the regulation and function of mPGES-1 and NLRP3 inflammasome were investigated. The expression of extracellular matrix proteins and the components of NLRP3 inflammasome were detected by Western blotting or real-time quantitative PCR.Results: In PD patients with ultrafiltration failure (UFF), mPGES-1 was enhanced in the peritoneum, which was associated with the degree of peritoneal fibrosis. Accordingly, the intraperitoneal PGE2 levels were also positively related to the PD duration, serum C-reactive protein levels, and serum creatinine levels in incident PD patients. In RPMCs, high-glucose treatment significantly induced mPGES-1 expression and PGE2 secretion without affecting the expressions of mPGES-2 and cPGES. Inhibition of mPGES-1 via short hairpin RNA significantly ameliorated the expression of extracellular matrix proteins of RPMCs induced by high glucose. Additionally, high glucose markedly activated NLRP3 inflammasome in RPMCs that was blunted by mPGES-1 inhibition. Furthermore, silencing NLRP3 with siRNA significantly abrogated the expression of extracellular matrix proteins in RPMCs treated with high glucose. Finally, we observed increased IL-1β and IL-18 levels in the dialysate of incident PD patients, showing a positive correlation with PGE2.Conclusion: These data demonstrate that mPGES-1-derived PGE2 plays a critical role in PD-associated peritoneal fibrosis through activation of the NLRP3 inflammasome. Targeting mPGES-1 may offer a novel strategy to treat peritoneal fibrosis during PD.
Highlights
Peritoneal dialysis (PD) has become a well-established treatment option for patients with end-stage renal disease due to the advantages of its minimal requirements for technical support and better preservation of residual renal function [1]
We initially studied the expression of Microsomal prostaglandin E synthase-1 (mPGES-1) in the peritoneal tissue of inguinal hernia patients with normal renal function and PD patients with ultrafiltration failure (UFF)
Immunohistochemical analysis of the visceral peritoneum showed that mPGES-1 was expressed in residual mesothelial cells in ultrafiltration failure PD patients, while mPGES-1 was rarely expressed in inguinal hernia patients (Figure 1B)
Summary
Peritoneal dialysis (PD) has become a well-established treatment option for patients with end-stage renal disease due to the advantages of its minimal requirements for technical support and better preservation of residual renal function [1]. Longterm PD is limited because chronic exposure to bioincompatible PD fluid can lead to obvious peritoneal fibrosis [2] These changes in the peritoneum include the loss of the mesothelial monolayer, thickening of the submesothelial layer because of increased deposition of the extracellular matrix, and angiogenesis [3,4,5]. High levels of inflammatory cytokines in the peritoneal cavity seem to be associated with the progress of peritoneal fibrosis [9]. As the first protection against biochemical and microorganism attack, peritoneal mesothelial cells incur various injuries and secrete inflammatory cytokines or chemokines, leading to the synthesis of extracellular matrix proteins and progression to peritoneal fibrosis [10, 11]. The role and mechanism of mPGES-1 in peritoneal dialysis (PD)-associated peritoneal fibrosis have not been investigated
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